Project Abstract Although the artemisinin-combination therapies (ACTs) are the most important drugs for the treatment of uncomplicated malaria, fundamental questions are unanswered including which ACT choice and dose is best for HIV-infected and HIV-uninfected children. In our first funding cycle we focused on artemether-lumefantrine as the most commonly prescribed ACT in Uganda and generated striking results that showed the pharmacokinetic (PK) exposure of lumefantrine, the compound most important for preventing new infections, can range by 10-fold depending on which HIV antiretroviral (ART) an HIV-infected child is receiving. Likewise, the artemisinins were also impacted, with efavirenz-based ART dramatically reducing both the artemisinins and lumefantrine. The contrasting effects seen with various ART led to significant differences in malaria clinical outcomes. Moreover, we studied HIV-uninfected children and learned that underweight children are also susceptible to important PK and pharmacodynamic (PD, exposure-response) distinctions. For our renewal we will focus on three aims. First we will determine the PK/PD of an extended artemether-lumefantrine dosing regimen in HIV-infected children on efavirenz-based ART that is designed to improve the PK exposure and treatment efficacy of this ACT regimen. Second, we will extend our studies to investigate, for the first time, the PK of another first line ACT, dihydroartemisinin-piperaquine, in HIV-infected children, who are on first-line ART. Third, we will determine the impact of specific classifications of malnutrition on the PK/PD of artemether-lumefantrine and dihydroartemisinin-piperaquine in HIV-uninfected young children and directly compare children who are underweight or stunted (the two most common forms of malnutrition in Uganda) to children with normal growth indices. Our overarching goal continues to be to inform the best treatment guidelines for young children in Africa. HIV-infected and HIV-uninfected children will be enrolled for intensive PK studies, as well as additional children for population PK studies to enhance association analyses with clinical outcomes. As for our first funding cycle, this proposal will leverage the outstanding infrastructure available in Tororo, Uganda and will benefit from the highly complementary expertise of Drs. Aweeka and Parikh who will continue to serve as joint-PIs.